The [N-(1-phenylcyclohexyl)piperidine (or PCP), developed as an anesthesic agent then withdrawn due to its very significant psychotopic effect, is today no more than a pharmalogical tool, interesting at least through its derivatives or analogues. One of the derivatives, N-(1-(2-thienyl)cyclohexyl)piperidine (or TCP), is, in its tritiated form, a ligand often used as a label for the PCP receptor. In vitro and in vivo studies of the [3H]TCP bond to the PCP receptor has revealed the existence of a second type of bond corresponding to the said PCP sites of low affinity in comparison to the first said sites of high affinity (Brain Res., 378, 133-141(1986)).
The present invention relates to novel derivatives of phencyclidines with selective affinity for low affinity receptors, processes for their preparation, pharmaceutical compositions containing them and their use as protective agents for central or peripheral nervous system cells against acute or chronic degeneration or as an anticonvulsant.
Therefore the subject of the invention is the compounds of formula I characterized in that they correspond either to formula IA
in which
Ar represents a carboxcylic or heterocyclic aryl radical, monocyclic with 5 or 6 members or constituted by condensed rings, and optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radicals, having at most 6 carbon atoms; free esterified or salified carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms;
R1 and R2 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from the hydroxyl, free esterified or salified carboxy, cyano, nitro radicals, or R1 and R2 form with the nitrogen atom to which they are linked a 
xe2x80x83radical in which n represents an integer from 0 to 2 and R3 and Rxe2x80x23 identical or different represent a hydrogen atom, a halogen atom or a hydroxyl, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radical having at most 6 carbon atoms;
R4 has the same meaning as R3 or Rxe2x80x23;
X, Y and Z are such that at least one represents a sulphur or oxygen atom and the others represent a methylene radical,
with the exception of the compounds in which R3, Rxe2x80x23 and R4 each represents a hydrogen atom and
1) R1 and R2 form with the nitrogen atom to which they are linked a pyrrolidine radical, Ar represents a phenyl or 2-thienyl radical and one of X, Y and Z represents an oxygen atom,
2) R1 and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, thienyl and benzothienyl radical, Y represents a sulphur atom and X and Z each represent a methylene radical,
3) R1 and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl, benzothienyl or 2-thienyl radical, Y represents an oxygen atom and X and Z each represent a methylene radical,
4) R1 and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl, methoxyphenyl or 2-thienyl radical, one of X or Z represents an oxygen atom, the other represents a methylene radical and Y represents a methylene radical,
5) R1 and R2 form with the nitrogen atom to which they are linked a piperidine radical, Ar represents a phenyl or 2-thienyl radical, one of X or Z represents a sulphur atom, the other represents a methylene radical and Y represents a methylene radical,
6) R1 and R2 form with the nitrogen atom to which they are linked a pyrrolidine radical, Ar represents a 2-thienyl radical, one of X or Z represents a sulphur atom, the other represents a methylene radical and Y represents a methylene radical,
7) R1 and R2 form with the nitrogen atom to which they are linked an ethylamino or pyrrolidine radical, Ar represents a phenyl radical, Y represents a sulphur atom and X and Z each represent a methylene radical,
or one of the following formulae:
xe2x80x94N-[1-(2-thienyl)-cyclohexan- 1-yl]-3-hydroxymethyl-piperidine,
xe2x80x94N-[1-(2-thienyl)-cyclohexan- 1-yl]-4-hydroxy-3-methyl piperidine,
xe2x80x94N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,
xe2x80x94N-ethyl-1-(2-thienyl)-cyclohexylamine or
xe2x80x94N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,
said compounds of formula I being in all possible racemic, enantiomeric and diastereoisomeric isomer forms as well as the addition salts with mineral and organic acids or with mineral and organic bases of said compounds of formula I.
A more particular subject of the invention is the compounds of general formula IA as defined below in which
Ar represents an heterocyclic aryl radical, monocyclic with 5 members or constituted by two condensed rings, and optionally substituted by one or more identical or different alkyl or alkenyl radicals;
R1 and R2, identical or different, represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms or R1 and R2 form together with a nitrogen atom to which they are linked a 
radical in which n is equal to 1 and R3 and Rxe2x80x23, identical or different, represent a hydrogen atom or a hydroxyl. aklyl or hydroxyalkyl radical having at most 6 carbon atoms.
In the definitions indicated above, the expression halogen represents a fluorine, chlorine, bromine or iodine atom.
The expression alkyl having at most 6 carbon atoms represents a linear or branched alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.
Among the alkenyl radicals. The linear or branched alkyl radicals such as vinyl, allyl, 1-propenyl, butenyl, pentynyl or hexynyl radicals can be mentioned.
Among the alkynyl radicals, the ethynyl, propargyl, butynyl, pentynyl or hexynyl radicals can be mentioned. The linear or branched alkoxy radical preferably designates the radicals in which the alkyl radical is as defined above. The methoxy, ethoxy, propoxy, isopropyloxy or butoxy radicals are preferred.
The alkylthio radical preferably designates the radicals in which the alkyl radical is as defined above such as for example methylthio or ethylthio.
The haloalkyl radical preferably designates the radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above such as, for example, bromoethyl, trifluoromethyl, trifluoroethyl or also pentafluoroethyl.
The hydroxyalkyl radical preferably designates the radicals in which the alkyl radical is as defined above such as for example hvdroxymethyl or hydroxyethyl.
The aryl radical can be carbocyclic or heterocyclic. The heterocyclic aryl radical can contain one or more identical or different heteroatoms chosen from oxygen, nitrogen and sulphur atoms. As an example of a carbocyclic or heterocyclic aryl radical, the phenyl. naphthyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, diazolyl, oxadiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl or indolyl radicals can be mentioned.
A more particular subject of the invention is the compounds of general formula IA as defined above in which
Ar represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl or allyl radicals;
R1 and R2 identical or different represent a hydrogen atom or a methyl or ethyl radical, or
R1 and R2 form with the nitrogen atom to which they are linked a 
radical in which n is equal to 1 and R3 and Rxe2x80x23 identical or different represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical.
More particularly, a subject of the invention is the compounds of formula IA described hereafter in the examples, in particular the compounds corresponding to the following formulae:
xe2x80x94N-[4-(2-thienyl)-3-methyl-tetrahydro-4H -thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;
xe2x80x94N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;
xe2x80x94N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-hydroxy piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine
in all the possible racemic, enantiomeric and diastereoisomeric isomer forms as well as the addition salts with mineral and organic acids or with mineral and organic bases of said compounds.
A subject of the invention is also a preparation process for the compounds of general formula I as defined above, characterized in that it comprises
the reaction of a compound of formula I 
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3 represent a sulphur or oxygen atom or a methylene radical, R4 has the meaning indicated above, with an aryl magnesium halide of formula Ar-Mg-Hal in which Hal represents a halogen atom and Ar has the meaning indicated above, in order to obtain the compound of formula 2
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3, Ar and R4 have the meanings indicated above,
the conversion of the hydroxyl radical of the alcohol of formula 2 thus obtained, to an azide of formula 3
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3, Ar and R4 have the meanings indicated above,
then the reduction of the acid azide of formula 3 in primary amine of formula 4 
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3, Ar and R4 have the meaning indicated above,
and finally, if the desired compound of formula I is such that at least one of the R1 or R2 radicals is different from the hydrogen atom or R1 and R2 form a ring with the nitrogen atom to which they are linked, the treatment of this compound of formula 4 in order to obtain the compound of formula I which is converted into the salt if desired.
In this preparation process, the first stage which consists of obtaining the compound of formula 2, is a standard Grignard reaction the implementation conditions of which are known to a person skilled in the art.
The second stage allows access to azide 3 from alcohol 2. The reaction takes place in the presence of an excess of an organic protonating agent such as trichloroacetic acid, an alkaline azide in a polar aprotic solvent. Preferably, the reaction takes place in the presence of an excess of trichloroacidetic acid and sodium azidide in chloroform.
For the reduction of the azides of formula 3 to the primary amine 4, standard methods known to a person skilled in the art for the reduction of azides can be used. The reduction can therefore be carried out using, for example, Raney nickel in isopropanol at 60xc2x0 C. or lithium aluminium hydride in diethylether or tetrahydrofuran.
If in the desired compound of formula I, R1 and R2 form a ring with the nitrogen atom to which they are linked, the fourth stage is then a cyclization; it is obtained by reacting, in a polar solvent, in an alkaline medium, the compound of formula 4 with the appropriate compound of formula Hal-(CH2)2xe2x80x94(CH2)n-(CH2)2-Hal or Hal-(CH2)xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)2-Hal of cis structure, substituted by the R3 and Rxe2x80x23 radicals, and in which n, R3 and Rxe2x80x23 have the meaning indicated above and Hal represents a halogen atom. The alkaline conditions allow the acid formed to be trapped and can be obtained by using, potassium carbonate for example. The polar solvent used can be chosen from methanol, acetone, hexamethylphosphoramide or sulpholane and preferably hexamethylphosphoramide.
The primary amine of formula 4 therefore corresponds to the compound of formula I in which R1 and R2 represent the hydrogen atom. If in the desired compound of formula I, R1 and R2 are identical or different and at least one of the two does not represent the hydrogen atom, then the compound of formula I is a secondary or tertiary amine depending on the values of R1 and R2; these amines can be obtained from the corresponding primary amine of formula 4 according to standard methods known to a person skilled in the art. Thus, for example, for the preparation of the compound of formula I in which one of the R1 or R2 radicals represents the hydrogen atom and the other an alkyl radical, the corresponding primary amine of formula 4 is reacted with the appropriate acid anhydride then the amide obtained is reduced with, for example, LiAlH4.
The different enantiomeric and diastereoisomeric isomer forms can be obtained by resolution either of the starting product or of the final product according to methods known to a person skilled in the art. For example, the two diastereoisomers can be separated in the final stage by simple chromatography. This separation can also be carried out after obtaining the compounds of formula 4. The resolution can also be carried out by using optically active acids such as tartaric or mandelic acids.
A subject of the invention is also another preparation process for the compounds of general formula I as defined above, characterized in that it comprises
the reaction of a compound formula 1 
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3 and R4 have the meaning indicated above, in an anhydrous medium, with a compound of formula R1R2NH in which R1 and R2 have the meanings indicated above, and a cyanide ion donor compound, in order to obtain the compound of formula 5
xe2x80x83in which Xxe2x80x3, Yxe2x80x3, Zxe2x80x3, R1 and R2 have the meanings indicated above, and
the reaction of the compound of formula 5 thus obtained, with an aryl magnesium halide of formula Ar-Mg-Hal in which Ar has the meaning indicated above and Hal represents a halogen atom, in order to obtain the compound of formula I according to the invention.
In this second preparation process, the reaction for obtaining the compound of formula 5 can be carried out in the presence of acetone cyanohydrin as cyanide ion doner; as a dehydration agent of the medium, anhydrous magnesium sulphate can for example be used. The reaction is preferably carried out in a polar basic solvent such as acetamide, methylacetamide, dimethylacetamide, acetylpiperidine or piperidine, and preferably dimethylacetamide or piperidine.
The second stage of this second preparation process is a Bruylants reaction (P. Bruylants, Bull. Soc. Chim. Belg., 33, 467 (1924); P. Bruylants, A. Castille, Bull. Soc. Chim. Beig., 34, 261-284 (1925)). On an experimental level, this reaction is stereospecific and leads to the introduction of the aryl radical in equatorial position. As a result, it will only be used for the synthesis of compounds of formula I not possessing a particular stereochemistry.
Taking into account the lack of stereospecificity of this first reaction. this synthesis route is preferentially used in the case where R4 represents a hydrogen atom.
The optional salification of the compounds of formula I is carried out according to the usual methods indicated hereafter in the experimental part.
The starting compounds of formula 1 in which R4 represents the hydrogen atom and Yxe2x80x3 represents a sulphur or oxygen atom or a methylene radical, are commercial products. The other starting compounds of formula 1 in which R4 represents the hydrogen atom, can be prepared according to the outline described by T. E. Young (J. Org. Chem., 38, 1562-1566 (1973)). The starting compounds in which R4 is different from the hydrogen atom, can be obtained from the corresponding compounds of formula 1 in which R4 represents the hydrogen atom, according to the substitution methods known to a person skilled in the art.
The compounds of the present invention have a very good affinity and selectivity for a new type of low affinity sites. The action on these sites inhibits the neurotoxicity induced by the glutamate responsible for certain pathological consequences such as acute or chronic degeneration of central or peripheral nervous system cells. The compounds of the present invention can thus be used in different therapeutic applications.
Thus the compounds of the present invention can be used to protect the central or peripherial nervous system cells against acute degeneration induced by accidents such as trauma, ischemia or the action of endogenic and exogenic neurotoxic agents, directly or by means of secondary mechanisms.
The compounds can also be used to protect the central or peripherial nervous system cells against chronic degeneration induced by neurodegenerative diseases and processes of pathological aging type, dementia, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis. They can also be used as anticonvulsants or antidepressants or to stimulate alertness, to treat states of dependency on different substances such as addictive drugs.
An illustration of the pharmacological properties of the compounds of the invention will be found hereafter in the experimental part.
These properties make the compounds of formula I suitable for pharmaceutical use. A subject of the present Application is, as medicaments, the compounds of formula I as defined above, in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with pharmaceutically acceptable mineral or organic acids or mineral or organic bases of said compounds of formula I, as well as the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
The invention thus relates to the pharmaceutical compositions containing a compound of the invention or an addition salt of a pharmaceutically acceptable acid or base of the latter, in combination with a pharmaceutically acceptable support. The pharmaceutical composition can be in the form of a solid, for example, powders, granules, tablets, gelatin capsules or suppositories. The appropriate solid supports can, for example, be calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound according to the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. The appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, similarly their mixtures, in varied proportions, in water, with pharmaceutically acceptable oils or greases added to them. Sterile liquid compositions can be used for intramuscular or sub-cutaneous injections and the sterile compositions can also be administered intravenously. The compositions according to the invention can also be administered by other standard routes such as oral administration.
A subject of the invention is also the use of the compounds of formula Ixe2x80x2 characterized in that they correspond either to formula Ixe2x80x2A 
in which
Arxe2x80x2 represents a carbocyclic or heterocyclic aryl radical, monocyclic with 5 or 6 members or constituted by condensed rings and optionally substituted by one or more identical or different radicals chosen from the halogen atoms, the hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radicals, having at most 6 carbon atoms; free esterifed or salified carboxy; cyano; nitro; amino optionally substituted by one or two identical or different alkyl radicals containing at most 6 carbon atoms;
Rxe2x80x21 and Rxe2x80x22 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms optionally substituted by one or more identical or different radicals chosen from the hydroxyl, free esterified or salified carboxy, cyano, nitro radicals or Rxe2x80x21 and Rxe2x80x22 form with the nitrogen atom to which they are linked a 
xe2x80x83radical in which n represents an integer from 0 to 2 and R3 and Rxe2x80x23 identical or different represent a hydrogen atom, a halogen atom or a hydroxyl, free esterified or salified carboxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl radical having at most 6 carbon atoms;
Rxe2x80x24 has the same meaning as R3 or Rxe2x80x23;
Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are such that at least one represents a sulphur or oxygen atom or a methylene radical and the others represent a methylene radical,
or one of the following formulae:
xe2x80x94N- [1-(2-thienyl)-cyclohexan-1-yl]-3-hydroxymethyl-piperidine,
xe2x80x94N-[1-(2-thienyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine,
xe2x80x94N-[1-(2-benzothiophenyl)-cyclohexan-1-yl]-4-hydroxy-3-methyl piperidine or
xe2x80x94N-ethyl-1-(2-thienyl)-cyclohexylamine,
xe2x80x94N-[1-(2-furyl)-cyclohexan-1-yl] piperidine,
xe2x80x94N-[1-(2-thienyl)-cyclohexan-1-yl]-3-methyl-piperidine,
said compounds of formula Ixe2x80x2 being in all possible racemic, enantiomeric and diastereoisomeric isomer forms as well as the use of addition salts with mineral and organic acids or with mineral and organic bases of said compounds of formula Ixe2x80x2,
for the preparation of medicaments intended to protect the central or peripherial nervous system cells against acute degeneration induced by accidents such as trauma, ischemia or the action of endogenic or exogenic neurotoxic agents, directly or by means of secondary mechanisms.
The invention also relates to the use of the compounds of formula Ixe2x80x2 as defined above, for the preparation of medicaments intended to protect the central or peripherial nervous system cells against chronic degeneration induced by neurodegenerative processes or diseases of pathological aging type, dementia, Alzheimer""s disease, Parkinson""s disease, amyotrophic sclerosis, as well as anticonvulsants or antidepressant medicaments or medicaments to stimulate alertness, to treat states of dependancy on different substances such as addictive drugs like cocaine.
The invention more particularly relates to the use of compounds of formula Ixe2x80x2A as defined above in which
Arxe2x80x2 represents a heterocyclic aryl radical, monocyclic with 5 members or constituted by two condensed rings and optionally substituted by one or more identical or different alkyl or alkenyl radicals;
Rxe2x80x21 and Rxe2x80x22 identical or different represent a hydrogen atom or an alkyl radical having at most 6 carbon atoms or R1 and R2 form with the nitrogen atom to which they are linked a 
xe2x80x83radical in which n is equal to 1 and R3 and Rxe2x80x23 identical or different represent a hydrogen atom or a hydroxyl, alkyl or hydroxyalkyl radical having at most 6 carbon atoms, for the preparation of medicaments as defined above.
The invention also relates more particularly to the use of the compounds of formula Ixe2x80x2A as defined above in which
Arxe2x80x2 represents the thienyl, furyl, benzothienyl, benzofuryl radical and optionally substituted by one or more methyl, ethyl, propyl or allyl radicals;
Rxe2x80x21 and Rxe2x80x22, identical or different, represent a hydrogen atom or a methyl or ethyl radical, or
R1 and R2 form with the nitrogen atom to which they are linked a 
xe2x80x83radical in which n is equal to 1 and R3 and Rxe2x80x23, identical or different, represent a hydrogen atom or a hydroxyl, hydroxymethyl, hydroxyethyl, methyl or ethyl radical, for the preparation of medicaments as defined above.
More particularly, a subject of the invention is the use of compounds of formula Ixe2x80x2A and corresponding to the following formulae:
xe2x80x94N-[4-(2-thienyl)-3-methyl-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;
xe2x80x94N-[4-(2-benzothiophenyl)-tetrahydro-4H-thiopyran-4-yl]-3-methyl-piperidine;
xe2x80x94N-[4-(2-furyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-benzofuranyl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(5-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(4-methyl-thiophen-2-yl)-tetrahydro-4H-thiopyran-4-yl]-piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]l-3-hydroxy piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl]-4-hydroxy piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-thiopyran-4-yl] piperidine;
xe2x80x94N-[4-(2-thienyl)-tetrahydro-4H-pyran-4-yl] piperidine;
xe2x80x94N-[3-(2-thienyl)-tetrahydro-4H-thiopyran-3-yl] piperidine;
for the preparation of medicaments as defined above.
The following examples are presented in order to illustrate the above procedures and must in no case be considered as a limit to the scope of the invention.